Despite the enormous value of antipsychotic medication in the treatment of schizophrenia, a large proportion of patients fail to derive substantial benefit from traditional medications. These patients experience considerable psychosocial and vocational dysfunction as well as persistent psychopathology. Their treatment remains an enormous public health challenge. Clozapine has proven to be superior to standard medications in the management of these patients. The data from our present study confirm and extend this conclusion to a longer time frame under double-blind conditions. Risperidone is now being perceived by many as a potential gateway to, or substitute for, clozapine. A direct comparison of these medications is sorely needed to provide guidance to the field as to their respective roles. This application requests four years funding for the following studies: Study l is a 29-week, double- blind comparison of clozapine and risperidone in moderately treatment refractory patients. Each center will randomize 60 patients providing a total sample of 90 receiving clozapine and 90 receiving risperidone. Study 2 will involve 60 patients at each site who would usually be excluded from such a controlled clinical trial, but who will participate in a separate randomization to the identical treatment conditions allowing an evaluation of the generalizability of the findings from Study l to the broader population of patients likely to be seen in the community. Study 3 will recruit from the same target population who fulfill entry criteria for either Study l or 2, but who do not agree to participate in either trial. Many of these patients will ultimately receive the drugs of interest and will be followed naturalistically utilizing a subset of the measures being employed in Studies 1 and 2. We expect to enroll three groups of 40 patients at each site receiving clozapine, risperidone or conventional antipsychotics (for a total of 360 additional patients). Assessment measures will include psychopathology, adverse effects, psychosocial functioning and measures of cognition. The results of these trials will have significant public health implications for the treatment of a large segment of the schizophrenia population.